The adaptations observed in the mesolimbic DA system of Girk1−/− and Girk2−/− mice may reflect synaptic scaling, a form of homeostatic plasticity triggered by persistent alterations in factors that influence neuronal excitability (Turrigiano and Nelson 2004; Kato et al. 2007; Thiagarajan et al. 2007). Synaptic scaling, manifest as an increase in the synaptic expression of GluR1 and GluR2-containing AMPA receptors, has been reported in the NAcc during cocaine withdrawal (Boudreau and Wolf 2005; Boudreau et al. 2007; Kourrich et al. 2007; Boudreau et al. 2009). Similarly, we observed elevated synaptic levels of both GluR1 and GluR2/3 in VTA DA and NAcc medium spiny neurons in Girk1−/− and Girk2−/− mice. It is possible, therefore, that the enhanced synaptic AMPA receptor distribution and elevated glutamatergic neurotransmission in VTA DA neurons and NAcc medium spiny neurons from Girk1−/− and Girk2−/− mice reflects compensatory responses of these neurons to persistent inhibition.
